The Computational Core is comprised of research components from the laboratories of Dr. Irwin Kuntz, UCSF and Dr. David Case, Scripps. There are two major aims of the Core. First, it will support the four research projects that form the proposal. Specifically, it will assist in the discovery and optimization of inhibitors for HIV Integrase, help with the design of peptidomimetics for Dr. Frankel's RNA-related projects, use molecular computation to explore the basis of drug resistance in HIV protease in collaboration with Dr. Craik, and assist in scaffold design and virtual screening for inhibitors of AphD from drug-resistant TB. The second major aim of the Core is to conduct research and development on basic drug design and drug discovery tools. To this end, it will carryout further extensions of the new release of the DOCK program, DOCKS. It will explore improved solvation and free energy computations using continuum solvent models. It will develop new methods for scaffold discovery and library design. Work between the Kuntz and Case groups will be allocated based on the expertise of each group, with the Kuntz group concentrating on discovery and early phase optimization and the Case group focusing on high quality assessments of binding free energies.